Chronic inflammation observed in obesity has been implicated in the development of medically important complications, particularly atherosclerosis, cancer, insulin resistance and non-alcoholic fatty liver disease. Macrophages, key mediators of inflammation, have been shown to contribute significantly to the development of these disorders. Despite considerable attention, however, there is little information thus far on the mechanism through which macrophages are differentially regulated by various inflammation- related adipokines (e.g., adiponectin and resistin) secreted by adipocytes. Is there a common molecular mediator in macrophages for various adipokines? Do various adipokines signal through distinctive pathways in macrophages? Remarkably, our recent data support the notion that macrophage TORC2 (for Transducers Of Regulated CREB activity 2) controls macrophage activation via a unique mechanism, involving nuclear-cytosolic shuttling of TORC2, upon stimulation by specific adipokines. Our two hypotheses are: (i) the adipokine signaling pathways mediated by adiponectin and resistin converge on macrophage TORC2; (ii) nuclear-cytosolic shuttling of TORC2 determines whether macrophages are activated, an event which controls inflammation and influences the pathophysiology of insulin resistance. These hypotheses place TORC2 as the key player that links systemic inflammatory effects of obesity to insulin resistance. Using the state-of-art biochemical and immunological approaches together with metabolic phenotyping, we will test these hypotheses with the following three Specific Aims: (1) to delineate the signaling pathway by which adipokines regulate TORC2 activity in macrophages, focusing on identification of the responsive kinase and phosphatase; (2) to validate the physiological importance of TORC2 in inflammation and insulin resistance in a macrophage-specific transgenic mouse model expressing a constitutively active TORC2 mutant; (3) to further elucidate the role of TORC2 in inflammation and insulin resistance in a loss-of-function TORC2 mouse model generated using bone marrow transplantation. Confirmation of the hypotheses will identify key molecules required for adipokine signaling of the macrophages and intracellular events leading to macrophage activation. Relevance to human health: Delineating the signaling pathway(s) will establish a pivotal mechanism for obesity- induced insulin resistance and related chronic diseases. It will provide one or more candidate targets for drug intervention in conditions exacerbated by chronic inflammation, and possibly establish TORC2 or its interacting partners as early markers of the onset of chronic inflammation. PUBLIC HEALTH RELEVANCE: This proposal investigates the molecular basis of adipokine signaling in macrophages in the context of obesity and its-related inflammatory disorders including atherosclerosis, cancer and diabetes. Delineating the signaling pathway(s) will establish a pivotal mechanism for obesity-induced insulin resistance and related chronic diseases. It will provide one or more candidate targets for drug intervention in conditions exacerbated by chronic inflammation, and possibly establish TORC2 or its interacting partners as early markers of the onset of chronic inflammation.